Although significant advances have been made in the outcome of children with ALL, one in four children will relapse. Not only are better therapies needed, but there also need to be better methods for deciding among new therapies. The presence of minimal residual disease (MRD) following therapy has been shown to be an important prognostic factor in childhood ALL. In this study we propose to use minimal residual disease to evaluate the effectiveness of several blocks of intensive therapy for children with ALL undergoing first marrow relapse. We will employ a flow cytometric method, extended from our experience on MRD testing on nearly 2000 children with newly diagnosed ALL. This method is based on the principle that leukemic B cells have phenotypes that can be distinguished, in multiparameter analysis, from those of normal B cell precursors. We will use this method to determine the kinetics of reduction of leukemic burden after each of 3 blocks of therapy, and compare these results to conventional methods of outcome, including day 8 marrow response, remission reinduction rates, and 4 month EFS. We will also compare these results to those obtained with a novel 8-colorflow cytometric method, hypothesizing that the latter will be more sensitive, and thus able to provide better quantitative information on the rate of leukemic clearance further into therapy. Finally, following the completion of this first study, we will perform the same analyses in a group of patients who will receive the anti-CD22 monoclonal antibody epratuzamab during block 1 but who otherwise receive identical therapy, and determine if there is a change in frequency of MRD that correlates with a change in outcome. If these studies prove successful, we will adapt this approach to the evaluation of numerous new agents superimposed on this same treatment backbone. We will also be able to extend these studies to other situations where we can use MRD as a rapid means to compare therapies.